下调和上调
KEAP1型
内质网相关蛋白降解
未折叠蛋白反应
内质网
癌症研究
平衡
细胞生长
信号转导
细胞生物学
细胞
化学
生物
氧化应激
生物化学
转录因子
基因
作者
Yanfeng Liu,Shishi Tao,Lijuan Liao,Yang Li,Hongchang Li,Zhihuan Li,Lilong Lin,Xiaochun Wan,Xiaolu Yang,Liang Chen
标识
DOI:10.1038/s41467-019-14190-2
摘要
Abstract Tumor cells often exhibit augmented capacity to maintain endoplasmic reticulum (ER) homeostasis under adverse conditions, yet the underlying mechanisms are not well defined. Here, through the evaluation of all human TRIM proteins, we find that TRIM25 is significantly induced upon ER stress. Upregulation of TRIM25 ameliorates oxidative stress, promotes ER-associated degradation (ERAD), and reduces IRE1 signaling in the UPR pathway. In contrast, depletion of TRIM25 leads to ER stress and attenuates tumor cell growth in vitro and in vivo. Mechanistically, TRIM25 directly targets Keap1 by ubiquitination and degradation. This leads to Nrf2 activation, which bolsters anti-oxidant defense and cell survival. TRIM25 expression is positively associated with Nrf2 expression and negatively with Keap1 expression in hepatocellular carcinoma (HCC) xenografts and specimens. Moreover, high TRIM25 expression correlates with poor patient survival in HCC. These findings reveal TRIM25 as a regulator of ER homeostasis and a potential target for tumor therapy.
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